The present invention is directed to the provision of compounds having potent anti-inflammatory and anti-oxidant activity. The invention is further directed to compositions containing the compounds of the present invention for use in pharmaceutical applications. The invention is also directed to methods of using the compounds and compositions of the present invention to prevent and treat inflammatory disorders including ocular inflammation associated with ophthalmic disease and ophthalmic surgery.
Inflammation from cellular stress can cause excessive tissue damage. Numerous biochemical pathways are known to lead to inflammation. In general, the cyclooxygenase system produces prostaglandins, while the lipoxygenase system produces leukotrienes, "HETEs" and "HPETEs." Such agents have been associated with inflammation. See generally, Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 600-617, Pergman Press, NY (1990). Therapies designed to inhibit the production of these types of agents are therefore of great interest.
Non-steroidal anti-inflammatory agents (NSAIA) have been used for the treatment of inflammatory disorders. The following references may be referred to for further background concerning this use of NSAIAs:
Ophthalmoscope, volume 8, page 257 (1910); PA1 FASEB Journal, volume 1, page 89 (1987); and PA1 Inflammation and Mechanisms and Actions of Traditional Drugs, vol. I Anti-inflammatory and Anti-rheumatic drugs. Boca Raton, Fla., CRC Press, (1985). PA1 Archives of Pharmacology, volume 325, pages 129-146 (1992); PA1 Journal of Photochemistry and Photobiology, volume 8, pages 211-224 (1991); PA1 Free Radicals in Biology and Medicine, volume 11, pages 215-232 (1991); and PA1 European Journal of Pharmacology, volume 210, pages 85-90 (1992). PA1 R is C.sub.1 -C.sub.3 alkyl; PA1 R' is (CH.sub.2).sub.m X'; PA1 m is 1 to 6; PA1 X' is OH, OR, NH.sub.2, NHR or H; PA1 n is 1 to 2; and PA1 X is O, S or NC(O)R. PA1 R is CH.sub.3 ; PA1 m is 1 to 2; PA1 X' is H or OH; and PA1 X is O.
However, there are some problems associated with NSAIA treatment including delivery to the appropriate site of action and side effects (Goodman and Gilman's The Pharmacological Basis of Therapeutics, pages 638-669, Pergman Press, NY (1990)).
Free radical molecules also play a major role in inflammation. These unstable chemical moieties lead to the oxidation of tissue resulting in damage. Such oxidative stress and damage has been described in Biochemical Pharmacology, 32(14), pages 2283-2286 (1983) and Free Radicals in Biology and Medicine, 4, pages 225-261 (1988). Agents that act as anti-oxidants can protect against oxidative damage. Such protection has been the subject of numerous scientific publications, including the following:
The combination of anti-oxidant activity with other pharmacologically significant activities in a single molecule is discussed in JP 64-40484 and EP 387771 A2; and compounds with cyclooxygenase/5-Lipoxygenase and anti-oxidant activity are discussed in Drug Research, 39(II) Number 10, pages 1242-1250 (1989). However, these references do not disclose the compounds of the present invention.
The present invention is directed to the provision of new compounds that have both potent anti-inflammatory activity and potent anti-oxidant activity in a single molecule. The use of a single chemical entity with potent anti-inflammatory and potent anti-oxidant activity provides increased protection relative to the use of a compound with singular activity. The use of a single agent having both activities over a combination of two different agents provides uniform delivery of an active molecule, thereby simplifying issues of drug metabolism, toxicity and delivery.